RT Journal Article
SR Electronic
T1 Hybrid of DNA-targeting Chlorambucil with Pt(IV) Species to Reverse Drug Resistance
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 221
OP 239
DO 10.1124/jpet.117.243451
VO 363
IS 2
A1 Feihong Chen
A1 Gang Xu
A1 Xiaodong Qin
A1 Xiufeng Jin
A1 Shaohua Gou
YR 2017
UL http://jpet.aspetjournals.org/content/363/2/221.abstract
AB Two hybrids of Pt(IV) species were designed and prepared by addition of a chlorambucil unit to the axial positions of the Pt(IV) complexes derived from DN603 and DN604. In vitro studies of two hybrids against two pairs of cisplatin sensitive and resistant cancer cell lines indicated that compound 5 had superior antitumor activity to cisplatin and chlorambucil via suppressing DNA damage repair to reverse drug resistance. Mechanistic investigation suggested that the potent antitumor activity of compound 5 arose from its major suppression of CK2-mediated MRE11-RAD50-NBS1(MRN) complex promotion of DNA double-strand break (DSB) repair. In nude mice with A549/CDDP xenografts, compound 5 exhibited higher anticancer efficacy than cisplatin and chlorambucil by reversing drug resistance, displayed improved effectiveness, and had no toxicity effects. Overall, compound 5 is a promising drug candidate, which could promote the anticancer activity and reverse drug resistance by attenuating CK2-induced MRN-dependent DSB repair.